Crystal forms of an anti-sars CoV-2 agent
The present invention features crystalline forms of Compound I, including polymorphs and pseudopolymorphs, which are useful in the preparation of pharmaceutical compositions.
1 . A crystalline Form 1 of Compound I,
wherein said crystalline form is characterized by an x-ray powder diffraction pattern having characteristic peaks at values of two theta (° 2θ) of 6.9, 8.3, 10.8, 11.9, 13.2, 13.7, 14.5, 15.4, 16.1, 18.2, 19.2, 20.0, 20.6, 21.7, 22.3, 23.9, 24.8, 25.2, 25.3, 26.1, 26.7, 27.6, 27.9, 28.9, 29.3, 30.1, 31.3, 31.3, 31.7, 32.5, 32.9, 34.7, 35.0, 35.8, 36.1, 36.8, 37.1, 37.8, 38.8, and 39.7.
2 . The crystalline form of claim 1 , further characterized by a differential Scanning Calorimeter thermogram having an Endotherm at 251° C. with an onset temperature at 250° C.
3 . The crystalline form of claim 1 , wherein said crystalline form is characterized by a differential Scanning Calorimeter thermogram having an Endotherm at 175° C. with an onset temperature at 175° C. and endotherm at 251° C. with an onset temperature at 250° C.
4 . A crystalline Form 2 of Compound I,
wherein said crystalline form is characterized by an x-ray powder diffraction (XRPD) pattern having characteristic peaks of two theta (° 2θ) of 6.9, 10.8, 11.9, 13.7, 14.5, 16.1, 18.1, 20.0, 20.6, 21.7, 22.3, 23.9, 24.8, 25.2, 26.1, 26.7, 27.9, 28.8, 29.2, 30.1, 31.3, 32.8, 34.3, 34.7, 35.77, 36.1, 37.1, and 39.9.
5 . The crystalline form of claim 4 , wherein said crystalline form is further characterized by a differential Scanning Calorimeter thermogram having an Endotherm at 175° C. with an onset temperature at 175° C. and endotherm at 251° C. with an onset temperature at 250° C.
6 . A crystalline Form 3 of Compound I,
wherein said crystalline form is characterized by an X-ray powder diffraction (XRPD) pattern having characteristic peaks at values of two theta (° 2θ) of 7.1, 8.7, 8.9, 11.0, 11.7, 13.1, 14.1, 15.2, 15.6, 16.2, 17.1, 17.5, 18.0, 19.2, 19.6, 20.4, 20.7, 21.9, 22.6, 23.5, 23.8, 24.7, 25.8, 26.3, 27.0, 28.1, 28.6, 29.7, 30.4, 31.3, 31.8, 32.3, 32.8, 33.3, 34.7, 35.6, 36.1, 36.5, 37.1, 37.9, and 38.2.
7 . A crystalline Form 4 of Compound I,
wherein said crystalline form is characterized by an X-ray powder diffraction (XRPD) pattern having characteristic peaks at values of two theta (° 2θ) of 4.4, 5.1, 7.1, 7.5, 8.5, 8.9, 9.8, 10.1, 10.3, 11.0, 11.7, 12.5, 13.1, 13.8, 14.1, 14.6, 14.8, 15.4, 15.8, 16.0, 16.9, 17.5, 17.9, 18.5, 19.2, 19.7, 20.1, 21.0, 21.8, 22.5, 23.4, 24.2, 24.9, 25.1, 26.2, 26.5, 27.8, 28.5, 29.4, and 31.0.
8 . A composition comprising a crystalline form according to claim 1 .
9 . A process for making a pharmaceutical composition comprising Compound I, comprising dissolving the crystalline form according to claim 1 in a solvent.
10 . A process for the preparation of the crystalline Form 1 of claim 1 ,
said process comprising the steps of:
1) preparing a solution of Compound I by dehydrating (3R,5'S)-1′-(N-methyl-N-(4,6,7-trifluoro-1H-indole-2-carbonyl)-L-leucyl)-2-oxospiro[indoline-3,3′-pyrrolidine]-5′-carboxamide (Compound n) in the presence of a suitable dehydration reagent or reagents, a suitable base, and a suitable solvent, thereby producing a solution of Compound 1;
2) concentrating the solution of Compound I from step 1 at a temperature from about 20° C. to about 80° C., to a solvent/Compound n ratio by volume (milliliter)/weight (gram) from about 2:1 to about 6:1;
3) optionally adding about 0.0001X (X=weight of Compound n in step 1) to about 0.1X of Form 1 of Compound I by weight to the concentrated solution from step 2, to induce crystallization of Form 1 of Compound I;
4) exchanging the solvent to a suitable solvent to a solvent/Compound n ratio by volume (milliliter)/weight (gram) from about 6:1 to about 10:1, at a temperature from about 20° C. to about 80° C., and the said suitable solvent is selected from anisole, toluene, xylene, ethyl acetate, isopropyl acetate, and mixtures of two or more thereof;
5) cooling the solution produced in step (4) to a temperature of about 0° C. to about 50° C., thereby producing Form 1 of Compound I; and
6) Filtering the product of step 5) to provide Form 1 of Compound I.
11 . The process as claimed in claim 9 , wherein the solvent is selected from anisole, toluene, xylene, ethyl acetate, isopropyl acetate, and mixtures of two or more thereof.
12 . A process for the preparation of the crystalline Form 1 of claim 1 ,
said process comprising the steps of:
I. adding Compound I to a first solvent thereby producing a solution; wherein the Compound I used to produce the solution is a solid form of Compound I or a mixture of two or more solid forms;
II. removing a portion of the first solvent from the solution, and then adding more of the first solvent;
III. repeating removing a portion of the first solvent from the solution and adding more of the first solvent until a solution of Compound I is produced with residual solvent controlled at no greater than a predetermined value;
IV. adding a second solvent to the solution to precipitate the Form 1 of Compound I; and
V. isolating the Form 1 of Compound I by filtration.
13 . The process as claimed in claim 12 , wherein the first solvent is EtOH, isopropanol, acetone, ethyl acetate, isopropyl acetate, or methyl tert-butyl ether.
14 . The method of claim 12 , wherein the second solvent water or n-heptane.